1. Field of Invention
This invention relates to the treatment of local hemorrhage and tissue necrosis resulting from snake bite by the administration of .alpha.-mercapto-.beta.-aryl acrylic acids and the corresponding disulfides as well as their pharmaceutically acceptable salts.
2. Description of the Prior Art
Venomous bites and stings, particularly venomous snake bites, result in tens of thousands of deaths each year worldwide primarily in under-developed countries. In developed countries where access to medical facilities and subsequent treatment with antivenom is readily available, death resulting from snake envenomation is rare. Although antivenom therapy is largely successful in reducing the mortality associated with venomous snake bites, it is less effective in reducing local hemorrhage and tissue necrosis, prominent symptoms of envenomation. Frequently the local tissue necrosis subsequent to a snake bite may be so severe as to result in permanent disfigurement, impairment or, in extreme cases, loss of an affected extremity.
Venom of poisonous snakes, and other venomous animals, is comprised largely or completely of a complex enzymatic mixture. The hemorrhagic factors of snake venom, those enzymes which are responsible for hemorrhagic activity, have been found to be metal dependent. Elimination of Ca (II), Mg (II) and Zn (II) from these hemorrhagic factors by various metal chelators in vitro eliminates the hemorrhagic activity, Tu, A. T., Venoms:Chemistry and Molecular Biology, John Wiley & Sons, New York (1977). See also Bjarnason, J. B. and Tu. A. T., Biochemistry 17 (16) 3395 (1978); Ownby, C. L. et al., J. Clin. Pharm., 15 419 (1975); Friederick, C., and Tu., A. T., Biochem. Pharm. 20 1549 (1971).
Thus, a mixture of diethylenetriaminepentaacetic acid (DTPA) and procaine when injected within 15 minutes of envenomation or ethylenediaminetetraacetic acid (EDTA) when injected within 30 minutes of envenomation by snake in the vicinity of the bite is known to reduce local hemorrhage; however, these agents are without effect in reducing tissue necrosis or lethality. Ownby, C. L., et. al., supra. Holvey, D. N., ed., The Merck Manual of Diagnosis and Therapy, 13th Edition, Merck Sharp and Dohme Research Laboratories, Rahway, N.J., 1972, page 1987. Moreover, EDTA is contraindicated in the presence of a disturbed electrolyte balance, a condition not uncommon with many snake bite victims. At present no agent is known to be topically effective against the local hemorrhage and tissue necrosis caused by envenomation.
Mercapto acrylic acids and their disulfides are known to be potent inhibitors of various metal dependent enzymes. Wagner, J., et al., Can. J. Chem., 55, 4028 (1977). However, their utility as topically effective agents useful in reducing local hemorrhage and tissue necrosis resulting from snake envenomation, as described below, is quite unexpected.
The mercaptoacrylic acids and their corresponding disulfides are additionally disclosed at Rovazzoni, C. et al, Ann. Chem. (Rome) 52, 305-12 (1962), Chim. Abstr. 57:9833g; Haskel, et al, J. Med. Chem. 13, 697 (1970); Halestrap. A., Biochem. J. 148(1), 85 (1975) as well as in U.S. Pat. Nos. 4,124,718; 4,130,653; 4,169,149; 4,210,664; 4,210,665; and 4,226,882.